Recently polyethers of the type of poly(ethylene oxide) (PEO) and poly(ethylene glycol) (PEG) have found application in biological and pharmaceutical contexts because of properties including water solubility, biocompatibility e.g. non-thrombogenic, and terminal hydroxy groups to attach various entities including drugs, prodrugs and other biological agents.
These polyethers (PEO, PEG) have been used as outer arms in star polymers where the cores have been divinylbenzene (may be cross-linked), poly(ethylene imine), poly(amidoamines) and heptaphenyl. See for instance:
U.S. Pat. No. 5,275,838, Jan. 4,1994, Merrill; and PA1 U.S. Pat. No. 5,648,186, Jul. 15, 1997, Daroux et al. PA1 U.S. Pat. No. 5,225,521, Jul. 6, 1993, Spinu. PA1 U.S. Pat. No. 5,276,110, Jan. 4, 1994, Zhou et al. PA1 a) an inner structure having a central silane nucleus and, optionally, multiple carbosilane branches extending outwardly from the nucleus in a repetitive generational manner yielding silane termini; PA1 b) bridge moieties comprising groups selected from alkyl of at least 4 C atoms, cycloalkyl, aryl including aralkyl and alkaryl, and polyether and polysulfide of up to about 6 repeating units, the moieties having reactive groups enabling attachment of polymer arms thereto. PA1 (i) the modified dendrimer described in the previous paragraph except that the alkyl bridge moiety has at least 2C atoms, and PA1 (ii) outer arms comprising polymer chains selected from polyethers, polysulfides, polyesters and copolymers thereof, the arms being attached to the dendrimer at the sites of the bridge reactive groups. PA1 a) attaching bridge moieties to reactive silane sites in a silane or carbosilane dendrimer, the bridge comprising a group selected from alkyl, cycloalkyl, aryl, aralkyl, alkaryl, small polyether and small polysulfide, the bridges having reactive groups thereon; and PA1 b) reacting a selected form of the bridge reactive groups with one of: PA1 (1) --R--X; where R is selected from alkyl and cycloalkyl having from 4 to 18 C atoms; aryl, aralkyl and alkaryl having from 6 to 18C atoms; and X is hydroxyl, thiol, amine, carboxyl, aldehyde, halide or a protecting group therefor; PA1 (i) polymerizing selected monomer in situ with the silane or dendrimer serving as initiator, or by PA1 (ii) attaching selected preformed polymer chains at the reactive group sites. Preferably the polymer arms have terminal modifiable functional groups selected from hydroxyl, aldehyde or keto, amino, carboxyl and thiol. These terminal groups may have protecting groups as outlined above. PA1 a) for polyether arm: alkylene oxide, alkylene glycol,the alkylene have 2-4 C atoms; PA1 b) for polysulfide arm: alkylene sulfide, alkylene dithiol(analogous to the polyether); and PA1 c) for polyester arm: glycolic acid lactone (glycolide),lactic acid lactone occurring in L-, D-, DL-forms and racemic mixtures (lactide) and -caprolactone. PA1 a) Preformed polyether and preformed polysulfide: PA1 b) Preformed polyester: ester formation activated by dicyclohexylcarbodiimide.
Polyester arms formed by ring-opening polymerization of lactones, lactides and glycolides have been used with cores of polyesters, sugar type molecules or inositol, to form star polymers. See for instance:
Carbosilane dendrimers have been used as cores in hybrid dendrimer-star polymers. These dendrimers provide a non-polar and chemically inert scaffold that is advantageous when thermal and hydrolytic stability is required, and in hydrophobic environments. See for example:
When these carbosilane dendrimers, having peripheral silane termini, were used as cores with arms of poly(alkylene oxide), it was found that the core-arm interface was unduly susceptible to hydrolysis in some applications. It would be desirable to reconfigure this interface in order to reduce susceptibility to hydrolysis.
The periphery of carbosilane dendrimers having outer allyl silane groups, has been modified to introduce hydroxy groups by controlled oxidation. See Lorenz et al in: Macromolecules 28, 6657-6661 (1995). No outer arms of any type of polymer were incorporated in this reference.
We have studied modifying the outer surface of carbosilane dendrimers to reduce hydrolytic cleavage at the core-arm interface when arms of polyalkylene oxide and the like are used in hybrid dendrimer-star polymers.